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Pharmacology: Inhibition of prostaglandin biosynthesis, which has been demonstrated experimentally, is considered fundamental to its mechanism of action. Prostaglandins play a major role in the causation of inflammation, pain and fever.
Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.
In rheumatic diseases, the anti-inflammatory and analgesic properties of Diclofenac sodium elicit a clinical response characterized by marked relief from signs and symptoms e.g., pain at rest, pain on movement, morning stiffness and swelling of joints, as well as by an improvement in function. In post-traumatic and postoperative inflammatory conditions, Diclofenac sodium rapidly relieves both spontaneous pain and pain on movement and diminishes inflammatory swelling and wound edema. When used concomitantly with opioids for the management of postoperative pain, Diclofenac sodium significantly reduces the need of opioids.
Pharmacokinetics: Approximately 20 min after IM injection 75 mg of Diclofenac, a mean peak plasma concentration of 2.5 mcg/mL (8 micromole/L) is attained. The plasma concentration is in linear relation to the size of the dose. The area under the concentration curve (AUC) is about twice as large as it is following oral or rectal administration of a dose of equal size, because about ½ the active substance is metabolized during its 1st passage through the liver ("first-pass" effect) when administered via the oral or rectal route.
Diclofenac becomes bound to serum proteins at a rate 99.7%, chiefly to albumin (99.4%).
The total systemic clearance of Diclofenac in plasma is 263 ± 56 mL/min (min value ± SD). The terminal half-life in plasma is 1-2 hrs.
Pharmacokinetic behavior remains unchanged following repeated administration. No accumulation occurs provided the dosage intervals are observed. Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hrs after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hrs. Two hours after reaching the plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hrs.
The biotransformation of Diclofenac involves partly glucuronidation of the intact molecule but mainly single and multiple hydroxylation resulting in several phenolic metabolites (3'-hydroxy, 4'-hydroxy, 5-hydroxy-, 4'5-dihydroxy-, 3'-hydroxy-4'-methoxy-diclofenac). The latter is largely converted to glucuronide conjugates.
About 60% of the administered dose is excreted in the urine in the form of metabolites from one of these 2 processes; <1% is excreted as unchanged substance. The remainder of the dose is eliminated as metabolites through the bile in the feces.
No relevant age-dependent differences in the drug's absorption, metabolism or excretion have been observed.
In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of <10 mL/min, the theoretical steady-state plasma levels of metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In the presence of impaired hepatic function (chronic hepatitis, nondecompensated cirrhosis), the kinetics and metabolism of diclofenac are the same as in patients without liver disease.
